This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To explore the use of human neural progenitor stem cells (HNPSCs) genetically modified to deliver the trophic factor GDNF as a therapy for Parkinson's disease and compare its effects to in vivo delivery and unmodified HNPSCs. HNPSCs have been proposed as a source of cells for ex vivo gene therapy. We performed a pilot study using HNPSCs genetically modified to deliver the trophic factor GDNF to assess viability and safety in the monkey brain. Our results showed HNPSCs survival and production of GDNF in the monkey brain via genetically modified HNPSCs and restoration/protection of dopaminergic fibers in target areas. Based on this data, we started a second project with extensive behavioral testing comparing the effects of 1) lentiviral vectors delivering GDNF vs. 2) HNPSCs delivering GDNF vs. 3) HNPSCs alone vs. 4) control media. The impact of this study is that it assesses, side-by-side, in vivo vs. ex vivo, gene therapy for the delivery of trophic factors. It also assesses whether HNPSCs by themselves can affect neurodegeneration. These are key questions for the application of these new biological therapies for the treatment of Parkinson's disease and other neurodegenerative disorders. This research used Animal Services, CPI, Stem Cell Resource, and Pathology Services.